ศ.ดร.พญ. รวงผ้ึง สทุเธนทร์ศูนยร์วบรวมและวเิคราะห์เชื้อเอชไอวแีห่งประเทศไทยภาควชิาจุลชวีวทิยา คณะแพทยศาสตรศิ์รริาชพยาบาล

มหาวทิยาลัยมหิดล

HIV Pathogenesis Update 2011: Understanding the Role of Immune Activation

& Inflammation in HIV Infection

Implication for HIV Pathogenesis

HIV disease is not a slow disease (lentivirus; lenti = slow), It is fast and furious

The damage done during the first weeks is devasting and likely permanent

The adaptive immune response does not control primary infection: the infection is self-limiting

Intervention is necessary prior to symptoms… (vaccination or prophylactic drug therapy)

Mattapallil et al., Nature 434 (2005) Haase AT. Nature 2010;464:217-23.

Mechanisms of CD4 Depletion and Dysfunction

Direct Elimination of HIV-infected

cells by virus-specific immune responses

Loss of plasma membrane integrity because of viral budding

Interference with cellular RNA processing

impaired regenerative capacity, coupled with the destruction of essential hematopoietic progenitor cells

Indirect Syncytium formation Apoptosis (infected and

uninfected cells) bystander activation-

induced cell death (AICD)

chronic immune activation

Autoimmunity

3

Immune activation in HIV infection results from dysregulated innate and adaptive immune responses to HIV, microbial

products, coinfections and homeostatic signals

Ford et al. 2009

HIV/AIDS immunopathogenesis in acute HIV infection

Persistent immune activation plays a central part in driving immunopathogenesis and progression to AIDS

Early innate immune system: failing early recognition and control of infection is a

major importance in the pathogenesis of acute HIV infection,

allowing establishment of infection and profound damage to innate as well as adaptive immune activities, not least in the GALT

Immune activation in acute HIV infection

HIV‑associated immune activation established in early HIV‑1 infection from: direct viral infection of immune cells, pro‑inflammatory cytokine production by innate

cells translocation of microbial products into the blood

through damaged intestinal epithelium Th17/TReg cells imbalance chronic mycobacterial and viral co‑infections.

Innate immunity Innate immune activation

PRR-triggered inflammation and type I IFN production induced by HIV or opportunistic pathogens

HIV evades innate immune recognition at early stages to establish chronic infection allows some degree of innate PRR activation

at later stages, where immune activation plays a detrimental role for the host chronic immune activation

Innate IR difference in acute and chronic infection

Summary of differences between nonpathogenic (sooty mangabeys) and pathogenic (rhesus macaques) SIV

infection

Ford ES, Puronen CE and Sereti I. 2009,4:206–214

INNATE IMMUNE RECOGNITION AND ACTIVATION DURING HIV INFECTION

• Mogensen et al. Retrovirology 2010, 7:54• Dandekar S, George MD and Ba¨umler AJ. Th17 cells,

HIV and the gut mucosal barrier. Current Opinion in HIV and AIDS 2010, 5:173–178

• Derdeyn C, Hunter E, et al. 2005, 2010• ElHeda A and Unutmaza D. Th17 cells and HIV infection.

Current Opinion in HIV and AIDS 2010, 5:146–150• Haase AT. Nature 2010;464:217-23.

Time frame, sites and major events in vaginal transmission

Haase AT. Nature 2010;464:217-23.

Representation of viral transmission across the mucosal barrier

• 90% are initiated in the newly-infected heterosexual partner by a single genetic variant

• MSM has shown about 80% with maybe 20% having two, three, or four variants being transmitted.

Mucosal immunity to prevent HIV transmission

Target early virus (1 week) for vaccineand postexposure prophylaxis

Target cell availability

CD4+ T-cell, macrophages and dendritic cells (lying just beneath the epithelium and deeper submucosa)

resting CD4 T cells outnumber macrophages and dendritic cells by 4 to 5:1

HIV exposure at endocervical epithelium initiates signal that increases expression of MIP-3α in the epithelium that recruits pDCs

Mucosal HIV-1 epithelial signalling at mucosa

pDCs recruit, from PRRs activated MIP-1β, CCR5+ CD4+ T cells influxed by MIP-1α and MIP-1β Interferons and chemokines inhibit viral replication

Pre-existing vaginal inflammation also facilitates infection by thinning and disrupting the multilayered lining, and providing a pool of target cells for local expansion

Principles in PRR signalling and transcription of cellular genes and HIV provirus

• HIV pathogen-associated molecular patterns (PAMPs) Ξ Pattern recognition receptors (PRRs) stimulates intracellular signalling pathways (TLR7/8)---activation of transcription factors, NF-κB, IRF-1 (interferon regulatory factors) IFN-α , and AP-1 (antiviral and inflammatory genes) from pDCs and macrophage

•NF-κB and AP-1 also activate transcription of the HIV provirus LTR to induce viral replication.

DCs bridge innate and adaptive IR DCs express several receptors for recognizing viruses,

pattern recognition receptors (PRRs) such as the Toll‑like receptors (TLRs) and C‑type lectins.

DCs detect viruses in peripheral tissue sites and, following activation and viral uptake, migrate to draining lymph nodes, where they trigger adaptive immune responses and promote NK cell activation

Activated cDCs produce cytokines such as interleukin‑12 (IL‑12), IL‑15 and IL‑18. IL‑12 is crucial for cDCs to induce T helper 1 (TH1) cell responses, which subsequently promote the potent cytotoxic T lymphocyte (CTL) responses that are necessary for clearing virus‑infected cells

cDCs and pDCs during HIV infection

-CD11c+ myeloid dendritic cells (mDCs/cDCs): located in skin, genital/gut mucosa-plasmacytoid dendritic cells (pDCs, CD11clo): blood, thymus, inflamed skin and mucosa and lymph nodes

immunopathologyhigh HIV concentration--internalization of HIV through lengerin

Altfeld M, Fadda L, Frieta D, Bhardwig N. Nature reviews Immunology 2011;11:176-186

Activated cDCs produce cytokines IL‑12, IL‑15, IL‑18 IL‑12 is crucial for cDCs to induce T

helper 1 (TH1) cell responses, promote the potent cytotoxic T lymphocyte (CTL) responses

DCs following activation and viral uptake, migrate to draining lymph nodes, trigger adaptive immune responses and promote NK cell activation

Plasmacytoid Dendritic Cells (pDCs)

pDCs, CD11clo): may first encounter HIV during early local viral replication/spread.

• Express CD4, CCR5, CXCR4, can be Infected by HIV• Inhibit HIV replication by secrete type 1 IFN• IFN-α and IDO (enzyme indoleamine (2,3)-dioxygenase)—

reduce Th17, increase Treg• TLRs 7 for RNA viruses and 9 for unmethylated CpG

pDCs=HIV gp120 inhibit TLR9-mediated response: pDC activation, IFN-α secrete, cytolytic activity of NK cells

Acute HIV infection (< 3 Ms) pDCs amount indirectly correlate with HIV viral load Average no of pDCs in healthy = 2-18 cells/µL LTNP—high pDCs

pDCs action

PRRs (HIV RNA) signaling TLR7/8 on pDCs and macrophage to induce express IFN-α proinflammatory cytokines: IL-1, TNF-α, attract inflammatory cells

IFN-α from pDCs cause Anti-HIV activities

• Increase degradation of RNA• Arrest cell cycle progression• Increase antigen presentation• Induce apoptosis of HIV uninfected and infected CD4+ T cells via TRAIL

(tumor necrosis factor-related apotosis inducing ligand) Attract CCR5 CD4+ T lymphocytes Suppress Th17 cells Immune activation

IDO inhibits T-cell receptor (TCR)-triggered T-cell proliferation and can induce differentiation of naive CD4+ T cells into Tregs

Dysregulation of DCs in HIV‑1 infection Both cDCs and pDCs in blood decrease in HIV infection

From direct infection Apoptosis Redistribute DCs to lymphoid tissue

rapid decline in circulating DCs, particularly plasmacytoid DCs (pDCs), may be due to activation‑induced cell death

migration of activated DCs into lymphoid tissue, an increase in DC numbers is observed Produce IFN-α

depending on the stage of HIV infection, DCs may be affected by the microenvironment chronic HIV infection, monocytes have been shown to

upregulate programmed cell death protein 1 (PD1) and produce IL‑10

partial maturation of cDCs from chronic immune activation by microbial translocation

Innate immune detection of HIV PAMPs

Yan N, Lieberman J. Current Opinion in Immunology 2011;23:21-28

intracellular innate immuneDNA sensors:-TLR9, DAI, POL III/RIG-I, LRRFIP1,IFI16, and HMGB-cytosolic SET complex, three nucleases (Ape1, NM23-H1, and TREX1) and HMGB2 bind HIV DNA And protect integration-TREX1, the most abundant cellular exonuclease, alsoinhibits the innate immune response to HIV DNA in Tcells and macrophages by digesting excess HIV DNA

TREX1 (3’-5’ exonuclease) inhibits innate immune detection of HIV DNA by metabolizing nonproductive RT products

nascent HIV capsid (CA) protein interacts with host cyclophilin A (CYPA) to trigger IFN via an IRF3-dependent pathway in monocyte-derived DCs (MDDCs)

This innate immune detection of nascent CA appears to be Dc specific and does not occur in CD4+ T cells.

HIV manages to avoid triggering innate immunity is by not replicating efficiently in DCs.

HIV infection of DCs may become more efficient during chronic infection, when proinflammatory cytokines are elevated

Early innate immune responses to HIV‑1

Acute-phase proteins and cytokinesThe first detectable innate IR, occurring sometimes just

before T0, was an increase in the levels of some acute-phase proteins,

such as serum amyloid AThen, a cytokine response [proinflammatory cytokines

(IL‑1)] and also by extrinsic factors such as lipopolysaccharide (LPS)

and a rapid increase in plasma viraemia

T0 = time that viral RNA was first detectable (100 copies per ml)

McMichael AJ et al, 2010 Nature review Immunology

Early innate immune responses to HIV‑1

Viraemia increase and also cytokines and chemokines level IL‑15, type I IFNs and CXC‑chemokine ligand (CXCL10) increase rapidly but

transiently IL‑18, TNF, IFN-γ and IL‑22 increase rapidly and sustained at high levels, increase in IL‑10 is slightly delayed type I IFNs, IL‑15 and IL‑18 enhance innate and adaptive immune

responses cellular sources: infected CD4+CCR5+ T cells, activated DCs, monocytes,

macrophages, NK cells, NKT cells and HIV‑specific T cells

intense cytokine response during acute HIV infection may also promote viral replication and mediate immunopathology

Potential roles of the innate immune system during HIV infection

Microbial translocation is a cause of systemic immune activation in chronic HIV infection

Nature Med 2006;12:1365

HIV and innate immune activation - impact on viral control and immunopathology

PRR = Pattern-recognition receptorsPAMPS = Pathogen-associated molecular patterns

Effect of IFN-α Acute HIV infection Pos effect

Anti-viral (inhibit HIV replication)

Activate NK cells Initiate adaptive IR

Neg effect Recruit T cells to mucosal

infected sites

Chronic HIV infection Pos effect

Induce apoptosis of infected cells

Neg effect Persistently expressed

in chronic infection; causes CD4+ T cell

depletion; induces chronic

immune activation

NK cells and HIV infection NK cells promote antiviral and antitumour immunity by producing

proinflammatory cytokines (IL-10, IFN-γ) and by lysing infected or transformed cells

Natural killer (NK) cells are defined as CD3CD56+ lymphocytes NK cells interact with T cells and DCs to shape the magnitude and

quality of adaptive immune responses Activation of NK cells caused by

high levels of proinflammatory cytokines secreted by DCs and monocytes, including IL-15 and IFN-α

After this initial expansion of highly activated NK cells, NK cells become increasingly impaired, with persisting viral replication and disease progression

impairment of NK cell function with progressive HIV-1 disease is associated with an accumulation of CD56low NK cells that are anergic to stimulation

DC-NK cell cross talkcDCs/HIV reduce secretion of IL-12,IL-15, IL-18—reduce NK activity

Altfeld M, Fadda L, Frieta D, Bhardwig N. Nature reviews Immunology 2011;11:176-186

Prolong innate immunity

Seminal contributions to transmission

Exposure of cervical vaginal epithelium to semen (tolerance of allogeneic sperm) elicits increases in chemokines such as MIP-3α and pro-inflammatory cytokines (GM-CSF, IL-1, IL-6 and IL-8) that recruit neutrophils, dendritic cells, macrophages and lymphocytes, which accumulate beneath the cervical and uterine epithelium

a microenvironment conducive to transmission is created by the recruited cells, the immunosuppressive effects of TGF-β and prostaglandin E in semen, other transmission-enhancing factors in semen such as the amyloid fibres derived from prostatic acid phosphatase

The balancing act in innate defences

These innate antiviral and inflammatory defense at the same time may facilitate transmission by increasing target cell availability, creating conditions for highly efficient cell-to-cell

spread of infection (less sensitive to inhibition by interferon)

Mapping local expansion revealed growth by accretion of newly infected cells around foci of infected founder cells, and spread of infection along tracts of infiltrating inflammatory cells

Mucosal defenses

Th17/Treg

Shacklett BL. Curr Opin HIV AIDS 2010;5:128-34.

Impaired mucosal immune defenses in HIV-1 infection lead to systemic immune activation

Low perforin, high PD-1 (immune exhausation),E-cadherin ligate KLRG-1 inhibit CTL function

Proinflammatory cytokines, loss of Th17/Treg balanceleads to increased epithelial permeability to microbial products

MUCOSAL IMMUNIZATION Wegmann F. PLoSone 2011;6:e15861

Haase AT Annnual RevMed2011;127-139

Problems of adjuvant for mucosal immunization adjuvants for mucosal application may induce local

inflammation, potentially increasing the HIV-1 transmission risk by recruitment of activated CD4+ T cells

Need adjuvant that promote immune responses whilst maintaining a non-inflammatory environment.

PRO 2000 is an anionic polymer under investigation as a candidate microbicide and

ineffective at preventing HIV-1 transmission an excellent safety record for vaginal application with no

evidence for local toxicity or irritation suppress the generation of vaginal inflammatory

mediators in women Useful for formulating agent for vaginally-applied HIV-1

vaccine antigens

Polyanion binding to gp120 selectively and reversibly masks antigenic surfaces containing positive charges, including the V3 loop and the CD4-induced (CD4i)-surface

Trimeric rgp140-PRO 2000 complexes: vaccine formulation improve the antigenicity of gp140 by re-

directing immune responses towards more conserved neutralization-relevant surfaces,

increasing antigen residency time and immunogenicity.

Since basic amino acids form the cleavage sites of most protect the glycoprotein from proteolytic digestion, highly conformational and discontinuous conserved neutralization epitopes still intact

PRO 2000 Polyanion PRO 2000 enhance mucosal immunogenicity

of HIV-1 envelope glycoprotein (Env)-based antigens, promoting local and systemic immune responses.

Vaginal immunization with Env-PRO 2000 resulted in significantly increased titres of Env-specific mucosal IgA and IgG in mice and rabbits

PRO 2000 antagonized TLR4 activation, suppressing local production of inflammatory cytokines.

Since inflammation-mediated recruitment of viral target cells is a major risk factor in HIV-1 transmission, the immune modulatory and anti-inflammatory activities of PRO 2000 combined with its intravaginal safety profile suggests promise as an HIV-1 mucosal vaccine formulating agent.

Immunomodulary activity of PRO 2000. Mononuclear cells derived from the vagina-draining Inguinal lymph nodes of vaginally

immunized mice were cultured in the presence of 15 µg/ml of gp140

PRO 2000 inhibits LPS signalling and inhibits the TLR4-MD2-lipid A

interaction

Murine embryonic fibroblast (MEF) TLR reporter cells were activated: TLR2 agonist Pam3CSK4,

DCs-based HIV vaccinemyeloid DCs pre‑treated with inactivated HIV

enhances immune control of HIV in patients, need functionally intact antigen‑presenting cells are required to limit viral replication

Adjuvants and vaccine vectors that target cDCs and pDCs simultaneously could promote adaptive immunity and limit TReg cell induction in order to control virus entry at mucosal sites, as well as systemically

DCs-based HIV vaccine

DC‑based vaccine strategies that elicit HIV‑specific NK cell responses and stimulate the production of memory cells may be crucial for the success of future vaccines the speed with which HIV gains entry into cells, innate defences

need to be rapidly mobilized. DCs target to activate specific NK cells and promote

their cytolytic functions. NK receptors, such as KIR3DS1, are important for

controlling HIV disease, NK cells can develop into protective virus‑specific

memory cells

ACUTE HIV INFECTION: HIV SPREAD TO LYMPHOID TISSUE

Peak viraemia

Free virus and/or virus‑infected cells reach the draining lymph node, where they meet activated CD4+CCR5+ T cells, which are targets for further infection

This process is augmented by cDCs that bind and internalize virus through DC‑specific ICAM3‑grabbing non‑integrin (DC‑SIGn or CD209) and carry the virus to activated T cells

B cells may also be involved in the early spread of infection by binding the virus through the complement receptor CD21 (also known as CR2)

Peak viraemia

virus then replicates rapidly and spreads throughout the body to other lymphoid tissues, particularly gut‑associated lymphoid tissue (GALT), where activated CD4+CCR5+ memory T cells are present in high numbers

20% of CD4+ T cells in the GALT are infected in acute HIV‑1 infection

up to 60% of uninfected CD4+ T cells at this site become activated and die by apoptosis, resulting in the release of apoptotic microparticles that can suppress immune function

Immune activation

Activation of innate cells and B and T cells is a striking feature of acute HIV‑1 infection of humans and SIV infection of rhesus macaques

Immune activation is associated with early and extensive apoptosis of B and T cells, leading to the release of apoptotic microparticles into the blood

increased expression of tumour necrosis factor (TNF)‑ related apoptosis‑inducing ligand (TRAIL; also known as TNFSF10) and FAS ligand (also known as CD95l), which kill bystander cells and are immunosuppressive

Peak viraemia ~80% of CD4+ T cells in the

GALT can be depleted in the first 3 weeks of HIV‑1 infection

while HIV‑1 is replicating in the GALT and other lymphoid tissues, the plasma viraemia increases exponentially to reach a peak, usually more than a million RNA copies/ml of blood, at 14–21 days after SIV infection in macaques and at 21–28 days after HIV‑1 infection in human

Enteric pathogens infecting intestinal mucosa induce the activation of CD4 T cells to differentiate preferentially to CD4+ Th17 cell subtype.

Th17 cells: cytokines causes the downstream effects of Neutrophil

activation/recruitment, induction of antimicrobial

peptides and tight junction proteins,

allowing for clearance of pathogen without further bacterial dissemination.

Severe depletion of CD4+ T cells in the gut mucosa during primary HIV and SIV infection, ↓↓Th1 and Th17 CD4+ T and ↑ Treg cell subtypes

pDCs express IDO inhibits T-cell receptor (TCR)-triggered T-cell proliferation and can induce differentiation of naive CD4+ T cells into Tregs

Loss of Th17/Treg balance -- progressive disruption of the mucosal barrier, permitting increased translocation of the gut microbial flora

Treg produce TGF-β that promote tissue fibrosis and limit immune reconstitution

impairing the normal response to bacterial pathogens.

CD8+ T cell is highly activated and induces the killing of virus-infected cells

HIV+ activated CD4+ T cell

Th17 cells

Th17 cells enriched in the intestine migration of Th17 cells in Peyer’s patches and other related

tissues in the gut are dependent on expression of the CCR6 in mice and humans and C-type lectin-like receptor CD161, in humans

Th17 CD4+ T cells mediate protective inflammatory reactions to a variety of bacterial and fungal pathogens, an important role in the defense against microbes at mucosal surfaces

Th17 cells express CCR6, which directs homing of these cells to skin and

mucosal tissues IL23-R, CCR4, CCR5, CXCR3, gut homing receptor α4β7

Th17 cells: differentiation

Differentiation of Th17 cells caused by: exposure of naive CD4+ T cells to APC-derived polarizing

cytokines such as TGF-β, IL-6, IL-21, whereas IL-23 acts to stabilize the commitment of Th17 cells to this lineage

endogenous lipid mediators such as prostaglandin E2 (PGE2) and apoptotic signals

Master regulator of Th17 differentiation is transcription factor RORt and RORα

Role of Th17 cytokines in protection versus disease at the mucosal surfaces

Current Opinion in HIV and AIDS 2010,5:120–127

balance between protective and pathological manifestation of Th17 responses at mucosal sites that defines immunity or inflammation.

HIV-1 infected Th17 cells

CCR5+Th17 cells were efficiently infected with CCR5-tropic HIV and were depleted during viral replication in vitro

Engagement of α4β7 on CD4 T cells by gp120 leads to activation of lymphocyte function-associated molecule 1 (LFA-1) or αLβ2, facilitating formation of virologic synapses and increasing the efficiency of HIV infection

Peripheral blood of HIV-positive patients have shown a decreased Th17:Th1 ratio and loss of Th17/Treg balance

HAART 50% restoration of CD4+T cells in the GALT of some HIV-infected patients mucosal immune recovery was associated with a more

pronounced restoration of the Th17 CD4+ T cell subset than the Th1 subset in GALT

Th17 and Treg balance The balance between Th17 and regulatory T-cells may

be critical in determining immune activation “set point” loss of β7high cells in blood during SIV infection closely

parallels the depletion of lamina propria CD4+ T-cells Frequency of β7high CD4+ T-cells in blood may be used

as a surrogate marker to estimate loss or restoration of intestinal CD4+ T-cells, without the need for gut biopsy

partial restoration of gastrointestinal CD4+ T-cells is possible in patients on long-term ART.

Restoration appears to be impeded by factors contributing to immune activation and/or collagen deposition, and enhanced by durable control of viral replication.

HIV-1 infection: change in Th17/Treg ratio

Potential mechanisms and immunological consequences of Th17 depletion during HIV or SIV

infection

The elusive role of regulatory T cells in HIV infection

Tregs are capable of suppressing T-cell activation Benefit: suppressing overactivation,

diminishing ‘bystander apoptosis’ and T-cell loss

Harm: suppressing HIV specific T-cell responses and hindering viral clearance

Accumulation of Tregs has been reported in the lymph nodes and gut of viremic patients

Summary of differences between nonpathogenic (sooty mangabeys) and pathogenic (rhesus macaques) SIV

infection

Ford ES, Puronen CE and Sereti I. 2009,4:206–214

Potential intervention to decrease microbial translocation and Th17 depletion in HIV infection

Block microbial translocationdirectly

Block inflammatory consequences of microbial translocation

Restore Th17 cells

Luminal antibiotics

Bovine clostrum

Inhibition of Toll-like receptor activation(i.e., chloroquine)

Exogenous IL-17 or IL-23 administration(significant concerns about toxicity)

Interventions to decrease inflammatoryMicroenvironment

HIV-1 and cytokines

In vivo studies reported that the progression of HIV infection toward AIDS and the levels of plasma viremia are associated with decreased levels of IFN-α, IL-2, IL-12, and IL-13, although increased levels of IFN-γ, IL-7, and TGF-β

Effective anti-retroviral therapy decreasing plasma viremia has shown to be effective for the restoration of physiological IL-2 and IL-13 levels

Cytokines

IL-2, IL-7, IL-15, IL-21 stimulate the expression of PD1 (program death receptor) and of both of its ligands, PD-L1 and PD-L2 on the surface of immune cells

PD-L1 and PD-L2 are constitutively present on monocytes, macrophages and dendritic cells, and can be induced on activated T cells.

PD-L1, PD-L2 bind to PD1 and the interaction results ↑IL-10 production, with the consequent reduction of T cell proliferation

New cytokines, IL-18, IL-27, IL-32, important players in the immunopathogenesis of HIV infection.

Production of IL-7 by hepatocytes and the peripheral effects of this cytokine on immune cells

Durum SK, Mazzucchelli RI. Live from the liver: hepatocyte IL-7. Immunity 2009; 30:320–321.

‘New’ cytokines in HIV pathogenesis

Cytokine Biological effectsInterleukin-18

Interleukin-21

Interleukin-27

Interleukin-32

Augmented in HIV infection; impairment of NK cellquantity and function

Decreased in HIV infection; up-regulation of NK cell function (increased synthesis of perforin)

Potent anti-HIV activity, effects partiallyoverlapping with those of IFNα

IL32 silencing results in increased HIV replication;generation of an HIV-hostile milieu

Immune activation & immunopathogenesis

Persistent immune activation Increased turnover of T cells, monocytes and natural

killer (NK) cells, high levels of CD4 and CD8 T-cell apoptosis and polyclonal B-cell activation with hypergammaglobulinemia

IL-6, D-dimer, C-reactive protein (CRP), inflammation biomarkers, predict mortality in HIV-positive patients further revitalized interest in immune activation strongly predictive of HIV disease progression

immune activation in HIV Continuous CD4 T-cell loss and replenishment

eventually leads to immunodeficiency as the regenerative capacity of weary naive and central memory

cells gradually dwindles despite apparent excess of homeostatic cytokines in the peripheral blood and lymphoid tissue

Exhaustion of the T-cell ‘supply’ due to direct killing by the virus, virus-induced apoptosis, immunologic senescence, the architectural destruction of lymphoid organs from fibrosis

induced by TGF-β and other cytokines interfere with dendritic–T-cell interactions and access to homeostatic cytokines

EARLY IMMUNE SENESCENCE IN HIV INFECTION

Desai S, Landay A. Curr HIV/AIDS Rep 2010;7:4-10.

HIV-1-infected individuals experience similar immunologic changes as uninfected

elderly persons. osteoporosis, atherosclerosis, and neurocognitive decline

a reduction in T-cell renewal, together with a progressive enrichment of terminally differentiated T cells with shortened telomeres, occurs.

immune activation and inflammation gradually leading to immunosenescence (aging of the immune system)

HIV-infected individuals (median age, 56 years) with good immune reconstitution and viral suppression had immune changes comparable with older (median age, 88 years) HIV-uninfected individuals.

>99% of HIV-1 particles in the circulation are non-infectious virions--constant stimulation of the immune system and drives early senescence in HIV infection.

These noninfectious particles contribute to HIV-induced immunopathogenesis activate the innate and adaptive immune system to

release mediators of inflammation that are known to be associated with age associated co-morbidities.

Cells of the innate system (eg, monocytes, dendritic, and natural killer [NK] cells) are also activated by infectious and noninfectious HIV particles secrete inflammatory cytokines e.g.TNF-α, IL-1β, and IL-6

TNF-α), IL-1β, and IL-6 to be associated with non-AIDS-defining co-morbidities in HAART-suppressed patients

CD4+ and CD8+ in HIV infected individualsCD8+ T cell activation (HLADR+CD38+) was

significantly higher in HIV-infected patients Naïve CD4+ and CD8+ T cells

(CD45RA+CCR7+) were significantly reduced in HIV- infected patients and older HIV-negative individuals as compared to HIV-negative young controls, with proportional increase in terminally differentiated effector T cells (CD45RA+CCR7−).

CD4+ and CD8+ central memory Tcells (CD45RA−CCR7+) were significantly reduced in HIV infected individuals as compared to older HIV-negative individuals.

highly differentiated cells (CD28−/CD57+) T cells Less produce IL-2, shortening of telomere

lengths T cells approaching end stage senescence Loss of CD28 on CD4+ T cells alters its

capacity to help B-cell proliferation and antibody production, thus affecting vaccine responses in elderly..

Accelerated aging model in HIV infection:

1. Microbial translocation-----immune activation ------activated cells, clonal expansion----- differentiation and accumulation of nonfunctional end stage senescent cells.

2. Activated cells release inflammatory mediators, causing optimal and suboptimal inflammation associated with non-AIDS-defining comorbidities and premature aging

Long-lasting central memory CD4+ T cells (TCM)

Long-lasting central memory CD4+ T cells (TCM) might play a particularly important role in the control of HIV replication

Their expression of the chemokine receptor CCR7 and the selectin CD62L, TCM preferentially home to secondary lymphoid organs and readily proliferate and differentiate into effector cells in response to antigenic stimulation

long-lived, ensuring long-term immunological memory HIV infection is characterized by defects in the

generation and maintenance of TCM cells CD8+ TCM have a shorter half-life and are less

abundant in HIV-infected individuals than in controls

Long-lasting central memory CD4+ T cells (TCM)

Early treatment of SIV infection is associated with a restoration of CD4+ TCM cells in the gut, suggesting that a fraction of TCM cells generated during an acute infection could be preserved so as to constitute a functional pool when viral replication is suppressed by HAART

Increased frequency and survival capacity of high interleukin (IL)-2–producing CD4+ and CD8+ TCM cells were measured in elite controllers (ECs) (e.g., HLA alleles B27 and B57), a rare population of HIV-infected individuals who control viral replication in the absence of therapy

Both CD4+ and CD8+ TCM cells contribute to the natural control of HIV and suggest that a drug-free control of HIV replication may be achieved by preventing the elimination of these cells through early treatment interventions and specific vaccination strategies

Elite controllersa strong polyfunctional CD8+ T cell

response to essential immunodominant epitopes, resulting in effective granzyme B-mediated killing of HIV-infected T cells

Resistance of CD4+ TCM cells to viral infection

a virus-free TCM compartment may be a major correlate of protection during lentiviral infection, including for controlling reactivation from latent reservoirs

HIV–T cells dynamics

THE MACROPHAGE IN HIV-1 INFECTION: FROM ACTIVATION TO DEACTIVATION?

Herbein G, Varin A. Retrovirology 2010;7:33

Macrophage type 1 and type 2

type 1 macrophages (M1) activated by Th1 and proinflammatory cytokines (IFN-γ).

type 2 macrophages (M2) induced by Th-2 cytokines, IL-4 and IL-13, express anti-inflammatory and tissue repair properties. stop the expansion of the HIV-1 reservoir

IL-10 as the prototypic cytokine deactivation of macrophages lead to immune failure observed at the very late stages of

the HIV-1 disease.

Nef, Tat, Vpr

Th1/Ths shift, loss of IL-2 and IFN-γIL-10+++ (inhibit proinflmmatorycytokines

Activated and deactivated macrophage Shift from activated to deactivated macrophages

throughout the disease is observed parallel to a Th1 pro-inflammatory/Th2 anti-inflammatory switch depend on type of tissue

Intestinal mucosa and CNS environment: shift to deactivation

Vaginal mucosa: more permissive to HIV-1 replication and are activated by proinflammatory cytokines

M1/M2/Md macrophage polarization may represent a mechanism that allows macrophages to cycle between productive and latent HIV-1 infection

chronic immune activationhigher frequency of circulating T cells with

an activated phenotype as well as with increased levels of pro-inflammatory cytokines and chemokines

chronic CD4+ and CD8+ T cell activation ultimately leads to clonal exhaustion of memory T cell pools and also provides an increased frequency of target cells for viral infection, thus leading to increased viral loads and systemic dissemination

Acute immune activation in HIV infection results from dysregulated innate and adaptive immune responses to HIV,

microbial products,

IDO, indoleamine-2,3-deoxygenaseLFA-1, lymphocyte function-associated molecule 1;

HIV-1 infection develops with acute viremia and rapid depletion of CD4 T cells within mucosal-associated lymphoid tissues [MALT], particularly in gut lymphoid compartment

HIV-1-induced disruption of MALT results in intestinal fibrosis and translocation of microbial products across the intestinal mucosa into the peripheral circulation producing high plasma levels of lipopolysaccharide [LPS] and bacterial DNA that persist throughout chronic HIV-1 infection

Microbial translocation appears related to systemic leukocyte activation and elevated plasma levels of inflammatory proteins

Wallet MA et al., AIDS 2010;24:1281-90.

Chronic HIV infection Chronic HIV-1 infection is characterized by

progressive activation of CD4 and CD8 T cells, as well as CD14 monocyte/macrophages and gradual depletion of peripheral naïve and memory CD4 T cells.

microbial translocation is a causative factor for systemic T cell activation, CD4 T cell decline, and disease progression

natural SIV infection of sooty mangabeys that develop high levels of viral replication in the absence of systemic T cell activation, CD4 T cell decline, or microbial translocation

In HIV-1 infection, systemic immune activation drives viral replication generating a vicious cycle of viremia, immune activation, and CD4 T cell attrition that ultimately results in AIDS

Effective combination antiretroviral treatment [ART] rapidly suppresses viremia, restores peripheral CD4 T cells, reduces lymphocyte activation, and restores most immune functions

Lederman MM. 2007

• direct viral infection of immune cells, • pro‑inflammatory cytokine production by innate cells • translocation of microbial products• Th17/TReg cells imbalance• chronic mycobacterial and viral co‑infections.

Haase AT Annnual RevMed2011;127-139